Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma

Yuko Matsunaga, Hiromasa Inoue, Satoru Fukuyama, Hideyuki Yoshida, Atsushi Moriwaki, Takafumi Matsumoto, Koichiro Matsumoto, Yukari Asai, Masato Kubo, Akihiko Yoshimura, Yoichi Nakanishi

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Abstract

Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathways play a critical role in allergic asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on asthmatic responses in a mouse model and investigated the mechanism for its biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6 treatment during the challenge phase suppressed eosinophilia in bronchoalveolar lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To improve the efficacy of the JAK inhibitor, P6 was encapsulated in polylactic- coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13 levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge phase treatment with P6-PLGA were similar to those after a sham treatment, the eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum OVA-specific IgE were decreased, while IL-17-producing T cells were increased by P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6 strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6 activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by inhibiting Th2 inflammation and that application of PLGA nanoparticles improves the therapeutic potency of P6.

Original languageEnglish
Pages (from-to)261-267
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume404
Issue number1
DOIs
Publication statusPublished - 2011 Jan 7

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Keywords

  • Allergic asthma
  • JAK inhibitor
  • JAK-STAT
  • Nanoparticle
  • Th17
  • Th2
  • Treg

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Matsunaga, Y., Inoue, H., Fukuyama, S., Yoshida, H., Moriwaki, A., Matsumoto, T., Matsumoto, K., Asai, Y., Kubo, M., Yoshimura, A., & Nakanishi, Y. (2011). Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma. Biochemical and Biophysical Research Communications, 404(1), 261-267. https://doi.org/10.1016/j.bbrc.2010.11.104